Rheumatoid arthritis (RA), exemplary delay-type hypersensitivity (DTH) disease, is hard to be cured effectively, probably due to the differences of drug-sensitivity among patients' unique gene mutational background. Accordingly, personalized medicine would be the ultimate solution for tackling the drug-resistance problem and therefore, understanding the gene mutation profiling of patients would be a key for cocktailing the best personalized medicine protocol. COSMIC analysis showed that mutations on IκB kinase β (IKK-β) have been frequently reported in cancer patients that would probably lead to altered kinase activity, as well as serious immunological disorders such as deficiency of innate and acquired immunity. In addition, IKK-β plays a crucial role in the progression of inflammatory diseases and cancers, and therefore discovery of IKK-β inhibitors has become the most promising arena against inflammation and cancers. However, studies showed that mutations on existing drug binding sites, especially on cysteine residue, would abolish the kinase inhibitory effect of IKK-β inhibitor; because cysteine plays crucial role in protein's post-modification and functions. Accordingly, identification and characterization of IKK-β mutations especially on cysteine residues would be a key roadmap for understanding diseases pathogenesis and discovering personalized therapeutics.
Previously, it was reported a site directed mutagenesis in the genes encoding for IKK-β protein. Single point mutants with cysteine (C) residue replaced by alanine (A) includes C12A, C46A, C59A, C99A, C114A, C115A, C179A, C215A, C299A, C370A, C412A, C444A, C464A, C524A, C618A, C662A, C716A and C751A mutations. These site directed mutagenesis revealed that IKK-β C46A contributed to significantly increased kinase activity. To address the function of this mutant kinase in vivo, generating homozygous IKK-βC46A transgenic mice appears to be a promising in vivo model for examining inflammatory responses and anti-inflammatory potency of relevant agents.
In the presence of a mouse model carrying C46A mutation in IKK-β protein, it will enable a better characterization of the clinical phenotype, the pathogenetic mechanisms thereof, and to gather insights on possible novel therapies of DTH and other inflammatory or cancerous diseases mediated by this mutant protein.